Pruritus is a common symptom of skin diseases as well as a sign of an underlying systemic pathology. Pruritus is an unpleasant sensation in the skin that provokes a desire to scracth and may be acute (of short duration) such as the reaction to an insect bite or chronic (lasting for more than 6 weeks) such as in many inflammatory skin diseases. It is well known that patients with inflammatory skin diseases perceive pruritus as seriously compromising their quality of life.
Pruritus is mediated via free nerve endings of non-myelinated C-type nerve fibres in epidermis. These have been found to express neuropeptides, and the epidermal keratinocytes produce neuropeptides, receptors for neuropeptides, nerve growth factor, vanilloid receptors proteinase-activated receptor type 2 (PAR2) and voltage-gated ATP channels (M W Greaves, Curr. Allergy Asthma Rep. 10, 2010, pp. 236-242). Neuropeptides suchs as Substance P have been shown to increase the production and release of nerve growth factor from cultured keratinocytes, suggesting that interactions between the immune system and the nervous system are important in the development of inflammation including pruritus. Inflammatory skin diseases such as atopic dermatitis, contact dermatitis, psoriasis and urticaria are associated with increased production of cytokines, neurotrophins and neuropeptides that may exacerbate the pruritus (U. Raap et al., Curr. Opin. Allergy Clin. Immunol. 11, 2011, pp. 420-427). While neuropeptides such as Substance P are not considered crucial for the pathogenesis of inflammatory skin diseases such as atopic dermatitis, they do play an important role in the development and severity of the condition, for instance by provoking the itch-scratch cycle where scratching exacerbates the inflammatory symptoms of atopic dermatitis (J. Salomon and E. Baran, JEADV 22, 2008, pp. 223-228). Furthermore, an increase of dermal nerves and upregulation of receptors for neuropeptides, e.g. the neurokinin 1 receptor has been found in skin from psoriasis patients with pruritus as opposed to skin from psoriasis patients without pruritus (S-E. Chang et al., Br. J. Dermatol. 156, 2007, pp. 1272-1277).
It has also been found that other cell types resident in skin release mediators of pruritus. Thus, mast cells contain large amounts of histamine that are released on activation of the cells and induce pruritus by targeting histamine H1 receptors on nerve endings. Eosinophils which infiltrate inflamed skin in atopic dermatitis, urticaria and contact dermatitis produce and release neurotrophins such as nerve growth factor.
Current therapeutic treatments of pruritus include both topical and systemic medicaments. Topical treatments include emollients and barrier creams that are believed to act by improving the barrier function of the skin, corticosteroids that do not appear to be antipruritic in themselves but act by relieving the attendant skin inflammation. This may also be the case for calcineurin inhibitors such as tacrolimus which has been shown to reduce pruritus in atopic dermatitis patients. Histamine H1 antagonists have also shown effect against pruritus in atopic dermatitis patients, but exhibits systemic side effects in the form of drowsiness in a significant number of patients. Local anesthetics such as lidocain have been found to exhibit anti-pruritic properties (Patel and Yosipovitch, Expert. Opin. Pharmacother. 11(10), 2010, 1673-1682).
Systemic therapy of pruritus include oral antihistamines, antidepressants, neuroleptics and immunosuppressants such as cyclosporin. A neurokinin-1 receptor antagonist, aprepitant, which has been developed as an oral antiemetic drug for use to counteract the nausea and vomiting caused by chemotherapy or post surgery, has been found to relieve pruritus in patients suffering from Sézary syndrome by oral administration (Duval and Dubertret, New Engl. J. Med. 361, 2009, pp. 1415-1416) and in patients with atopic diathesis, prurigo nodularis and systemic pruritus (S. Stander et al., Plos One, 2010, p. 5).
WO01/25219 discloses piperazine derivatives which are antagonists of tachykinins, including substance P and other neurokinins.
WO02/32867 discloses piperidine derivatives which are antagonists of tachykinins, including substance P and other neurokinins
WO02/081457 discloses 1,4-diazepane-1-carboxylic acid derivatives process for their preparation and their use as tachykinin antagonists
WO2009002770 discloses 6.5 pyrrolopiperidine tachykinin receptor antagonists.
As many of the antipruritic treatments available at present have side-effects that may limit their use, and as many dermal conditions are preferentially treated with topical medications, especially when the conditions is of mild to moderate severity, there is a continued need to develop neurokinin 1 receptor (NK1R) antagonists which are effective in the treatment of itch on topical application, but which have reduced systemic effects on the central nervous system.